Bezlotoxumab associated with lower recurrence of C. difficile infection: The MODIFY I and II trials

1. Bezlotoxumab therapy associated with significantly lower rate of recurrent C. difficile infection compared to placebo.

2. Actoxumab not efficacious when administered aloine or in combination with bezlotoxumab in reducing rates of recurrent C. difficile infection.

Evidence Rating Level: 1 (excellent)

Study Rundown: In hospitalized patients, C. difficile is a widespread cause of infectious diarrhea. An emerging approach in preventing the recurrence of C. difficile infection involves co-administering toxin-neutralizing monoclonal antibodies along with standard of care of antibiotics. Actoxumab and bezlotoxumab are human monoclonal antibodies that target C. difficile toxins A and B, respectively. In the Monocolona antibodies for C. Difficile Therapy (MODIFY I and II) Trials, researchers aimed to determine the efficacy of administering both antibodies (with antibiotics) together, separately and against placebo in reducing rates of symptomatic C. difficile recurrence.

They found that bezlotuxumab was associated with a significantly lower rate of recurrent infection compared to placebo, with both having a similar safety profile. Additionally, in subgroup analysis, researchers also demonstrated that for participants categorized as high risk for recurrent infection (i.e. patients >65 years of age, immunocompromised), bezlotuxumab was similarly efficacious compared to placebo in preventing recurrent infection. In contrast, actoxumab failed to provide benefit in prevention C. difficile recurrence. Limitations of the study include lack of standardization of standard-of-care antibiotics and potential underestimation of severe baseline C. difficile infection, given many initial assessments were performed on patients already receiving antibiotics. Overall, this is a well-powered study with optimal follow-up that suggests neutralization of toxin B via bezlotoxumab may reduce disease recurrence.

Click to read the study, published today in NEJM

Relevant Reading: Recurrent Clostridium difficile infection: from colonization to cure

In-Depth [randomized controlled trial]: In these nearly identical double-blind, randomized, placebo controlled trials conducted between 2011 and 2015, 2655 adults receiving standard-of-care antibiotics to prevent C. difficile infection were randomized to receive either bezlotoxumab (n = 781), bezlotoxumab and actoxumab (n = 773), actoxumab (n = 232) and placebo (n = 773). Of note, only the MODIFY I trial included a single-therapy actoxumab group – the second trial excluded it due to it’s demonstrated lack of efficacy. The primary end point was recurrent infection, defined as a new episode after initial clinical cure within 12 weeks after treatment infusion. In the MODIFY I trial, for the bezlotoxumab-only and placebo groups, recurrence rates were 17% (67 of 386) and 28% (109 of 395), respectively (95%CI 15.9 to -4.3; p < 0.001). Similarly, in the MODIFY II trial, for the bezlotoxumab-only and placebo groups, recurrence rates were 16% (62 of 395) and 26% (97 or 378), respectively (95%CI 17.4 to -5.9; p < 0.001). The bezlotoxumab and actoxumab combination groups were also more efficacious in reducing recurrence compared to placebo. Rates of adverse events were similar between groups, with the most common events being abdominal pain, diarrhea and nausea.

Image: PD

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